The association of antiphospholipid (aPL) antibodies with thrombosis in patients with Antiphospholipid Syndrome (APS) is well documented in humans and in animal studies. However, the mechanism(s) by which these antibodies induce thrombosis is the subject of much current study. Previous studies have shown that aPL up regulate endothelial cells (ECs) adhesion molecules (CAMs): intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion-1 (VCAM-1) and E-selectin (E-sel) or induce tissue factor (TF) on monocytes. APL also induced activation of ECs and enhanced thrombus formation in vivo. One study suggested that the anti-hyperchlorestoralemic drug fluvastatin inhibited the enhanced adhesion of monocytes to ECs by aPL in vitro. What is uncertain is the molecular and intracellular events that are induced by aPL interaction with ECs leading to expression of CAM and TF. Other studies also suggest that aPL antibodies may activate platelets as demonstrated by increased expression of GPIIb/ IIIa when platelets are treated with aPL in the presence of an agonist. The intracellular events triggered by aPL interaction with platelets are also unknown. This study proposes to investigate the molecular and intracellular events of two important pathogenic mechanisms mediated by aPL: EC activation (up regulation of CAM and TF), and activation of platelets. First, whether aPL-mediated up-regulation of CAMs on ECs involves de novo protein synthesis, cytoskeleton movements, activation of NF-kappa-B, mitogen-activated protein kinase (MAP- kinase) and protein kinase C (PKC) and transcription of specific genes will be examined. Second, whether TF expression and function is affected by aPL on ECs and the intracellular mechanisms involved will be determined. The effects of the drug fluvastatin on the proadhesive and procoagulant effect of aPL on ECs invitro and in vivo experiments will be also studied. Third, the intracellular events involved in aPL-induced platelet activation and whether aPL effects on thrombosis in vivo are mediated by platelet activation (i.e. increase expression of GPIIb/ IIIa) will be determined. One strategy to examine the importance of aPL-induced platelet activation in thrombosis will be to utilize the anti-platelet drug abciximab, a platelet membrane GPIIb/ IIIa receptor antagonist which inhibits expression of GPIIb/ IIIa. This study will determine whether this agent inhibits aPL-induced thrombosis in mice. In another set of experiments beta-3-integrin deficient-mice (GPIIb/ IIIa knock-out mice) will be used to establish whether platelet activation is involved in enhanced thrombosis in vivo mediated by aPL/. Understanding the intracellular and molecular events in thrombosis associated with aPL is important and will provide significant information that may help to establish new ways of treatment and prevention of recurrences of thrombosis in APS patients.